A large number of serious diseases, such as AIDS, hepatitis B, herpes and gynecological cancer, as a late result of papilloma warts, are caused by viral infections.
Viruses are small infectious agents which are incapable of independent replication and thus are dependent on a host cell to replicate. The genetic material of the virus is either RNA or DNA.
When infecting an organism, the virus attaches to a specific host cell. The virus penetrates the cytoplasmic membrane after attachment and the viral genome is released from the virus particle. The viral genome is usually transported to the cell nucleus where new viral genomes are replicated. New viral protein is synthesized in the cytoplasm and new particles are formed either close to the cytoplasmic or nuclear membrane.
Some virus have genomic material which is directly (DNA viruses) or indirectly (Reverse transcription of RNA, retrovirus) incorporated in the host cell genomes.
Extracellular viruses are neutralized by circulating antibodies and the cellular immune apparatus may attack and remove infected cells. Viruses within the infected cells escape immune surveillance if viral antigens are not exposed on the surface of the cells.
The immune attack on infected organs contributes to disease by a mechanism commonly called virus induced immunopathology.
The mechanisms underlying some of the more important viral diseases differ.
When suffering from an HIV infection, the patient's T helper cells are invaded and destroyed. This leads to an immunodeficiency condition, which makes the patient very susceptible even to infections which normally are conquered by the immune system without any harmful effects for the patient.
The Hepatitis B virus invades the liver cells, and the patient may become very ill when the immune system tries to rid the body of these infected cells. If the infection is not conquered by the immune system at an early stage, the result will be chronic hepatitis. The patient will thus be infectious throughout his life. For a group of patients the chronic hepatitis will develop into cirrhosis or cancer of the liver.
In herpes simplex infections, the virus enters the epidermal cells originally. The herpes simplex virus travels up to a nerve center where it lies latent to break out at intervals. Although not life threatening in most cases, a herpes infection is painful and the patient will be infectious every time an outbreak occurs.
In the papilloma virus, notably in the genital tract of women, the viral genome is located in the nucleus of epithelial cells, but not integrated in the cell chromosomes. This is a persistent condition and with some tumor promoting strains an integration finally occurs which leads to a malignant development. The viral genome in this case has a decisive initiating effect in the process leading to cancer.
If the immune system manages to rid the body of the virus at an early stage, this leads to a life-long immunity. On the other hand, if the virus is too aggressive and avoids the immune apparatus, no immunity is achieved and a continuous infectious state is the result.
As a result of the different mechanisms, the therapeutic strategy would be different for these conditions.
The ultimate goal in the treatment of HIV/AIDS would be to free the patient from the infectious virus. This seems to be remote at the present stage, However, much can be obtained by improving the general condition of the patient. A reduction of the virus load would increase the length of the symptom free period and reduce the infectiousness, which is of utmost importance in regard to the epidemiological situation. All currently used anti-viral agents have toxic side effects, which presently makes a sufficiently aggressive treatment impossible.
It is assumed that there are between 250 and 300 million carriers of hepatitis B worldwide. It is known that a great number of these are going to develop hepatomas or liver insufficiencies due to the infections. Promising results in the treatment of the carrier state have been obtained in recent years by induction of an immune response with interferon. Therapies reducing the virus load is important in this regimen as efficient treatment of acute hepatits B would reduce the number developing into a carrier state. The recently identified hepatitis C virus causes a very great number of cases with hepatitis whereof a large number develop into carriers. Preliminary studies seem to indicate that the carrier state may be broken by similar therapeutic regimens as for hepatitis B.
Herpes simplex 1 and 2 frequently infect humans causing a carrier state with recurrencies of local infections. Generalized infections including encephalitis are rare but a catastrophy for the patient. There is a great individual variation in the frequency of local infections. For those patients who are affected either genitally or facially this constitutes a serious health problem physically, mentally and socially. None of the therapeutic regimens developed so far cures the latent infections of cells in the central nervous system. The therapeutic goal is thus to minimize the clinical manifestations of recurrencies both as to symptoms and duration.
The prevalence of genital papilloma virus infections has increased dramatically during the 1980s. It is now established that some genotypes are oncogenic, that is, they initiate changes in the cell which after a latency period develop into cancer. Papilloma virus of the genital tract gives long standing infections. The factors causing malignant transformation of the lesions are not well understood, but the immune system is assumed to be of importance. It is thought that the lesions showing progression during the months and years are those giving rise to cancer. The genital papillomas called condylomas are at present treated by physical means such as surgical removal, necrotizing means, fluid nitrogen or the like. Genital warts are at the onset benign tumors with altered enzyme patterns affecting among other things the metabolism of nucleoside analogues. Nucleoside prodrugs affect the episomal proliferation of papilloma virus thereby inducing regression of the warts.
Prophylactic vaccination has been very successful in acute infections such as polio, measles, mumps etc, but no effective vaccination has been developed for many of the other serious viral infections.
Even though there have been intensive efforts to produce effective anti-viral chemotherapeutica during the last decades, no satisfactory medical treatment can be offered for most viral diseases today. The efforts have been especially great since the appearance of the HIV and related viral infections, which are spreading throughout the world at an alarming rate, yet the effects obtained with agents such as azidothymidin (AZT) and acyclovir (ACV) in AIDS and herpes can only be characterized as partially successful. These most promising anti-viral agents are thus derivatives of naturally occurring nucleosides, which have been modified either in the base or sugar moiety. They have, however, not had the therapeutic potential hoped for, as they bring forward serious side-effects in some patients or show little or no effect in others. Further, treatment with these agents is extremely expensive. For these reasons only patients suffering from the very serious viral infections such as AIDS receive such treatment. Patients suffering from the less serious, but also very painful viral infections are often left without any treatment and the infection is allowed to take its own course.
The untreated patient carries a great infectious load and constitutes a risk to his fellow human beings. If he is treated with an anti-viral agent, the aim is to reduce the infectious load so as to enable the body's immune system to conquer the infection. A further aim is to reduce the contagiousness and thus the number of new patients and carriers.
Thus the need for compounds having a better therapeutic index is obvious.
The need is especially great in chronic or recurrent viral infections with a dangerous acute phase or long term ill effects on health or well being, such as AIDS, hepatitis B and C, infections of the herpes group and papilloma viral infections. Similarily, there is also a need for anti-viral agents usable in the treatment of animals suffering from viral diseases.